Asparaginase

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<scene name='52/525144/3eca_like_aw/1'>Text To Be Displayed</scene><StructureSection load='' size='300' side='right' scene='52/525144/Cv/1' caption='E. coli asparaginase I tetramer complex with aspartic acid, asparagine, ethylene glycol and Cl- ions (green), [[2p2n]]'>
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<StructureSection load='' size='300' side='right' scene='52/525144/Class_ii_3eca/2' caption='First Asparaginase structure (Class_II - [3eca]) dimer, [[3eca]]'>
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== Function ==
== Function ==
'''L-Asparaginases''' are enzymes that hydrolyze the amide group of the amino acid L-asparagine (L-Asn) to L-aspartate, with the simultaneous release of ammonia. They are often referred to as ASNase and assigned the EC number 3.5.1.1; if significant glutaminase co-activity (hydrolysis of the similar amino acid L-glutamine) is also present, the EC number is 3.5.1.38. Some ASNases that belong to other classes (see below) are assigned EC 3.4.19.5.
'''L-Asparaginases''' are enzymes that hydrolyze the amide group of the amino acid L-asparagine (L-Asn) to L-aspartate, with the simultaneous release of ammonia. They are often referred to as ASNase and assigned the EC number 3.5.1.1; if significant glutaminase co-activity (hydrolysis of the similar amino acid L-glutamine) is also present, the EC number is 3.5.1.38. Some ASNases that belong to other classes (see below) are assigned EC 3.4.19.5.
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*'''Glycosylasparaginase''' hydrolyzes the bond between asparagine and the sugar moiety in N-linked glycoproteins<ref>PMID:8638940</ref>.
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*'''Isoaspartyl peptidase/L-asparaginase''' enables aparaginase and beta-aspartyl-peptidase activity. Invovved in asparagine catabolic process via L-Asp <ref>PMID:15159592</ref>.
== Relevance ==
== Relevance ==
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== Structural studies ==
== Structural studies ==
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The first L-asparaginase structure was published and deposited in the PDB in 1993 for the EcAII enzyme <ref>PMID:8434007</ref> and may serve as an example of a Class 1 type II enzyme <scene name='52/525144/3eca_cartoon/5'>EcAII</scene> ('''Figure EcAII_3eca'''). Structure of Class 1 type I enzymes is exemplified by <scene name='52//Cv/1'>EcAI</scene><ref>PMID:17451745</ref>, whereas Class 2 type III enzymes may be represented by EcAIII<ref>PMID:15159592</ref><ref>PMID:18334484</ref> ('''Figure EcAIII_2zal'''). Class 2 L-asparaginases belong to the family of Ntn-hydrolases, which are expressed as inactive precursors that must undergo autoproteolytic cleavage into α and β subunits to achieve maturation<ref>PMID:35626629</ref>. While the existence of an alien type of ASNase in the symbiotic nitrogen-fixing bacterium ''Rhizobium etli'' had been recognized long ago<ref>PMID:11996000</ref>, the structure of the inducible and thermolabile prototype Class 3 ReAV was solved and deposited in the PDB only recently<ref>PMID:34795296</ref> ('''Figure ReAV_7os5'''), followed by structures of the constitutive and thermostable isoform ReAIV<ref>PMID:37494066</ref>. More than 200 structures of ASNases have been deposited in the Protein Data Bank (PDB) by April 2024<ref>PMID:34060231</ref> (Wlodawer et al., 2024).
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The first L-asparaginase structure was published and deposited in the PDB in 1993 for the EcAII enzyme <ref>PMID:8434007</ref> and may serve as an example of a <scene name='52/525144/Class_ii_5os5/2'>Class 1 type II enzyme EcAII</scene>. Structure of <scene name='52/525144/Class_i_8oww/2'>Class 1 type I enzymes is exemplified by EcAI</scene><ref>PMID:17451745</ref>, whereas <scene name='52/525144/Ecaiii_2zal/4'>Class 2 type III enzymes may be represented by EcAIII</scene><ref>PMID:15159592</ref><ref>PMID:18334484</ref>. Class 2 L-asparaginases belong to the family of Ntn-hydrolases, which are expressed as inactive precursors that must undergo autoproteolytic cleavage into α and β subunits to achieve maturation<ref>PMID:35626629</ref>. While the existence of an alien type of ASNase in the symbiotic nitrogen-fixing bacterium ''Rhizobium etli'' had been recognized long ago<ref>PMID:11996000</ref>, the structure of the <scene name='52/525144/Class_ii_5os5/2'>iducible and thermolabile prototype Class 3 ReAV</scene> was solved and deposited in the PDB only recently<ref>PMID:34795296</ref>, followed by structures of the constitutive and <scene name='52/525144/8sow/1'>thermostable isoform ReAIV</scene><ref>PMID:37494066</ref>. More than 200 structures of ASNases have been deposited in the Protein Data Bank (PDB) by April 2024<ref>PMID:34060231</ref><ref name="Wlodawer">Wlodawer, A., Dauter, Z., Lubkowski, J., Loch, J.I., Brzezinski, D., Gilski, M., Jaskolski, M. (2024) Toward a dependable dataset of structures for L-asparaginase research(submitted).</ref>.
== Evaluation of the ASNase structures in the PDB ==
== Evaluation of the ASNase structures in the PDB ==
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Evaluation of 189 structures of ASNases that were present in the PDB as of November 2023 was described in Wlodawer et al. (2024). Most structures did not raise any significant concerns. However, 30 models had various kinds of stereochemical problems and/or doubtful agreement with the experimental electron density maps. Consequently, they were re-refined in order to remove the shortcomings. The revised models (listed here) may be downloaded from this site in both the legacy PDB and mmCIF formats.
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Evaluation of 189 structures of ASNases that were present in the PDB as of November 2023 was described in Wlodawer et al. (2024)<ref name="Wlodawer" />. Most structures did not raise any significant concerns. However, 30 models had various kinds of stereochemical problems and/or doubtful agreement with the experimental electron density maps. Consequently, they were re-refined in order to remove the shortcomings. The revised models (listed here) may be downloaded from this site in both the legacy PDB and mmCIF formats.
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== Structural highlights ==
 
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<scene name='52/525144/Cv/3'>ASP I active site is located at the N terminal region in the interface between subunits</scene>.<ref>PMID:17451745</ref> Ligands asparagine (in white) and aspartic acid (in salmon) are shown in spacefill representation.
 
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*<scene name='52/525144/Cv/6'>Asparagine binding site</scene>, chain A. Water molecules shown as red spheres.
 
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*<scene name='52/525144/Cv/7'>Aspartic acid binding site</scene>, chain A.
 
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*<scene name='52/525144/Cv/8'>Cl coordination site</scene>.
 
==3D structures of asparaginase==
==3D structures of asparaginase==

Current revision

First Asparaginase structure (Class_II - [3eca]) dimer, 3eca

Drag the structure with the mouse to rotate

References

  1. ↑ Park H, Vettese-Dadey M, Aronson NN Jr. Glycosylation and phosphorylation of lysosomal glycosylasparaginase. Arch Biochem Biophys. 1996 Apr 1;328(1):73-7. PMID:8638940 doi:10.1006/abbi.1996.0144
  2. ↑ Prahl A, Pazgier M, Hejazi M, Lockau W, Lubkowski J. Structure of the isoaspartyl peptidase with L-asparaginase activity from Escherichia coli. Acta Crystallogr D Biol Crystallogr. 2004 Jun;60(Pt 6):1173-6. Epub 2004, May 21. PMID:15159592 doi:10.1107/S0907444904003403
  3. ↑ Egler RA, Ahuja SP, Matloub Y. L-asparaginase in the treatment of patients with acute lymphoblastic leukemia. J Pharmacol Pharmacother. 2016 Apr-Jun;7(2):62-71. PMID:27440950 doi:10.4103/0976-500X.184769
  4. ↑ Beckett A, Gervais D. What makes a good new therapeutic L-asparaginase? World J Microbiol Biotechnol. 2019 Sep 24;35(10):152. PMID:31552479 doi:10.1007/s11274-019-2731-9
  5. ↑ Ghasemian A, Al-Marzoqi AH, Al-Abodi HR, Alghanimi YK, Kadhum SA, Shokouhi Mostafavi SK, Fattahi A. Bacterial l-asparaginases for cancer therapy: Current knowledge and future perspectives. J Cell Physiol. 2019 Nov;234(11):19271-19279. PMID:30993718 doi:10.1002/jcp.28563
  6. ↑ Chan WK, Horvath TD, Tan L, Link T, Harutyunyan KG, Pontikos MA, Anishkin A, Du D, Martin LA, Yin E, Rempe SB, Sukharev S, Konopleva M, Weinstein JN, Lorenzi PL. Glutaminase Activity of L-Asparaginase Contributes to Durable Preclinical Activity against Acute Lymphoblastic Leukemia. Mol Cancer Ther. 2019 Sep;18(9):1587-1592. PMID:31209181 doi:10.1158/1535-7163.MCT-18-1329
  7. ↑ Hendriksen HV, Kornbrust BA, Østergaard PR, Stringer MA. Evaluating the potential for enzymatic acrylamide mitigation in a range of food products using an asparaginase from Aspergillus oryzae. J Agric Food Chem. 2009 May 27;57(10):4168-76. PMID:19388639 doi:10.1021/jf900174q
  8. ↑ Chand S, Mahajan RV, Prasad JP, Sahoo DK, Mihooliya KN, Dhar MS, Sharma G. A comprehensive review on microbial l-asparaginase: Bioprocessing, characterization, and industrial applications. Biotechnol Appl Biochem. 2020 Jul;67(4):619-647. PMID:31954377 doi:10.1002/bab.1888
  9. ↑ Loch JI, Jaskolski M. Structural and biophysical aspects of l-asparaginases: a growing family with amazing diversity. IUCrJ. 2021 Jun 30;8(Pt 4):514-531. PMID:34258001 doi:10.1107/S2052252521006011
  10. ↑ Michalska K, Jaskolski M. Structural aspects of L-asparaginases, their friends and relations. Acta Biochim Pol. 2006;53(4):627-40. Epub 2006 Dec 1 PMID:17143335
  11. ↑ Swain AL, Jaskolski M, Housset D, Rao JK, Wlodawer A. Crystal structure of Escherichia coli L-asparaginase, an enzyme used in cancer therapy. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1474-8. PMID:8434007
  12. ↑ Yun MK, Nourse A, White SW, Rock CO, Heath RJ. Crystal structure and allosteric regulation of the cytoplasmic Escherichia coli L-asparaginase I. J Mol Biol. 2007 Jun 8;369(3):794-811. Epub 2007 Mar 30. PMID:17451745 doi:http://dx.doi.org/10.1016/j.jmb.2007.03.061
  13. ↑ Prahl A, Pazgier M, Hejazi M, Lockau W, Lubkowski J. Structure of the isoaspartyl peptidase with L-asparaginase activity from Escherichia coli. Acta Crystallogr D Biol Crystallogr. 2004 Jun;60(Pt 6):1173-6. Epub 2004, May 21. PMID:15159592 doi:10.1107/S0907444904003403
  14. ↑ Michalska K, Hernandez-Santoyo A, Jaskolski M. The mechanism of autocatalytic activation of plant-type L-asparaginases. J Biol Chem. 2008 May 9;283(19):13388-97. Epub 2008 Mar 10. PMID:18334484 doi:10.1074/jbc.M800746200
  15. ↑ Linhorst A, Lübke T. The Human Ntn-Hydrolase Superfamily: Structure, Functions and Perspectives. Cells. 2022 May 10;11(10):1592. PMID:35626629 doi:10.3390/cells11101592
  16. ↑ Borek D, Jaskólski M. Sequence analysis of enzymes with asparaginase activity. Acta Biochim Pol. 2001;48(4):893-902 PMID:11996000
  17. ↑ Loch JI, Imiolczyk B, Sliwiak J, Wantuch A, Bejger M, Gilski M, Jaskolski M. Crystal structures of the elusive Rhizobium etli L-asparaginase reveal a peculiar active site. Nat Commun. 2021 Nov 18;12(1):6717. doi: 10.1038/s41467-021-27105-x. PMID:34795296 doi:http://dx.doi.org/10.1038/s41467-021-27105-x
  18. ↑ Loch JI, Worsztynowicz P, Sliwiak J, Grzechowiak M, Imiolczyk B, Pokrywka K, Chwastyk M, Gilski M, Jaskolski M. Rhizobium etli has two L-asparaginases with low sequence identity but similar structure and catalytic center. Acta Crystallogr D Struct Biol. 2023 Aug 1;79(Pt 8):775-791. PMID:37494066 doi:10.1107/S2059798323005648
  19. ↑ Lubkowski J, Wlodawer A. Structural and biochemical properties of L-asparaginase. FEBS J. 2021 Jul;288(14):4183-4209. PMID:34060231 doi:10.1111/febs.16042
  20. ↑ 20.0 20.1 Wlodawer, A., Dauter, Z., Lubkowski, J., Loch, J.I., Brzezinski, D., Gilski, M., Jaskolski, M. (2024) Toward a dependable dataset of structures for L-asparaginase research(submitted).

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